68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives

doi:10.1053/j.semnuclmed.2011.02.001

Seminars in Nuclear Medicine

Volume 41, Issue 4, July 2011, Pages 314-321

https://doi.org/10.1053/j.semnuclmed.2011.02.001 Get rights and content

In this review we give an overview of current knowledge of ⁶⁸Ga-labeled pharmaceuticals, with focus on imaging receptor-mediated processes. A major advantage of a ⁶⁸Ge/⁶⁸Ga generator is its continuous source of ⁶⁸Ga, independently from an on-site cyclotron. The increase in knowledge of purification and concentration of the eluate and the complex ligand chemistry has led to ⁶⁸Ga-labeled pharmaceuticals with major clinical impact. ⁶⁸Ga-labeled pharmaceuticals have the potential to cover all today's clinical options with ^99mTc, with the concordant higher resolution of positron emission tomography (PET) in comparison with single photon emission computed tomography. ⁶⁸Ga-labeled analogs of octreotide, such as DOTATOC, DOTANOC, and DOTA-TATE, are in clinical application in nuclear medicine, and these analogs are now the most frequently applied of all ⁶⁸Ga-labeled pharmaceuticals. All the above-mentioned items in favor of successful application of ⁶⁸Ga-labeled radiopharmaceuticals for imaging in patients are strong arguments for the development of a ⁶⁸Ge/⁶⁸Ga generator with Marketing Authorization and thus to provide pharmaceutical grade eluate. Moreover, now not one United States Food and Drug Administration–approved or European Medicines Agency–approved ⁶⁸Ga-radiopharmaceutical is available. As soon as these are achieved, a whole new radiopharmacy providing PET radiopharmaceuticals might develop.

Section snippets

Physical Characteristics of ⁶⁸Ge, ⁶⁸Ga, and the ⁶⁸Ge/⁶⁸Ga Generator

The theoretical ingrowth of ⁶⁸Ga from the parent nuclide ⁶⁸Ge in a ⁶⁸Ge/⁶⁸Ga generator is shown in Fig. 1 and Table 1. Already 68 minutes after the previous elution of the generator, 50% of the maximal activity of ⁶⁸Ga is reached, and after 4 hours this is >90% (Fig. 1). ⁶⁸Ga decays to 89% by positron emission and 11% via electron capture. The average positron energy per disintegration is 740 keV (E_max = 1.9 MeV), which is higher, for example, than that of ¹⁸F and potentially leads to lower

Purification and Eluate Concentration

The major limitations for direct use of ⁶⁸Ga for radiolabeling of DOTA-peptides for clinical PET applications are the large volume of generator eluate, high [H⁺], ⁶⁸Ge breakthrough, and potential metal ion impurities.7, 33, 34, 35 However, although the concentration of these metals (eg, Zn, Sn, Ti, and Fe) are low (ie, at sub parts per million level), their concentration can still be much higher than the concentration of ⁶⁸Ga. If one supposes a concentration of Zn²⁺, Sn⁴⁺, Ti⁴⁺, or Fe^2+/3+ of 1

⁶⁸Ge Breakthrough

Since the discovery of ⁶⁸Ge in fission products1, 2 and the possibility of medical application of ⁶⁸Ga, there has been renewed interest in its biochemical and pharmacologic properties. The presence of ⁶⁸Ge activity in the eluate of ⁶⁸Ge/⁶⁸Ga generator, although low, has frequently been an item of concern for clinical application of ⁶⁸Ga-labeled pharmaceuticals. Rosenfeld² reported studies on the metabolism of germanium in the 1950s. Metabolic studies on the absorption, transport, distribution,

DOTA-Peptides Labeled With ⁶⁸Ga

G protein–coupled receptors like somatostatin receptors are frequently overexpressed on human tumor cells.22, 45, 46 Somatostatin receptor–targeted imaging, initially with [¹²³I-Tyr³]octreotide and later with [¹¹¹In-DTPA⁰]octreotide (OctreoScan; Covedien, Hazelwood, MO), was important for imaging and diagnostics of neuroendocrine tumors in nuclear medicine.3, 7, 19, 47

Radiolabeled peptides targeting G protein–coupled receptors with DOTA as bifunctional chelator were developed and have shown in

PK of ⁶⁸Ga-labeled Pharmaceuticals

The uptake kinetics of ⁶⁸Ga-DOTA-peptides such as DOTATOC, DOTANOC, and DOTA-TATE (for structural formula see Fig. 2) are rapid11, 18 and in good agreement with the half-life of ⁶⁸Ga. The small size of these molecules displays desirable PK properties, because the process of binding with their G protein–coupled receptor is rapid, as well as their clearance, which are both required for successful imaging.⁵³

Other ligands that bind to G protein–coupled receptors, such as analogs of octreotide,

Specific Radioactivity

There are many factors that influence the interaction of a radioligand with its receptor. In saturable regulatory peptide binding processes (ie, in vitro radioimmunoassay and receptor binding), the signal-to-background ratio is often improved by increasing the specific radioactivity (expressed as activity units per mass units of ligand, eg, MBq per nmol) of the ligand. In in vivo experiments it was shown that contrary to what was expected, the percentage uptake of radiolabeled octreotide

Robotics for Automated Labeling

Initially all labeling procedures were done manually. Finger dosimetry measurements during elution of the generator and radiolabeling revealed doses of 60 μSv per 555 MBq and 1.5 mSv per administration of 10 MBq in rats.³⁵ Introduction of robotics increased reproducibility, and it also opened the routine application of ⁶⁸Ga-labeled analogs for radiopharmacies. The development of automated modules included reduction of ⁶⁸Ge activity, impurities, and volume in the ⁶⁸Ga activity containing eluate

Regulatory Affairs

Efforts to obtain approval for Marketing Authorization for radionuclide generators (such as the ⁶⁸Ge/⁶⁸Ga generator), labeling kits, etc have recently been reported.22, 23, 71, 72 Because the eluate of a ⁶⁸Ge/⁶⁸Ga generator is considered a medicinal product and all ingredients for clinical administration should be approved for pharmaceutical use, aspects such as the choice of a buffer for pharmaceutical use are also investigated and reported.²¹ Moreover, not only should the ingredients be of

Applications

Most neuroendocrine tumors express somatostatin receptor subtype 2.45, 46, 73 Somatostatin receptor–targeted imaging is important in nuclear medicine.

In general, analogs of octreotide have high affinities for somatostatin receptor subtypes 2, 3, and 5; however, there are differences in affinity per receptor subtype per analog. DOTANOC has very high affinity for receptor subtypes 2,3, and 5.10, 14, 19, 74, 75, 76 In an intraindividual clinical study comparing the diagnostic efficacy of ⁶⁸

Future Perspectives

In a review on the continuing role of radionuclide generator systems for nuclear medicine, Knapp and Mirzadeh⁸³ state that “despite the availability of the ⁶⁸Ge/⁶⁸Ga generator application of ⁶⁸Ga radiopharmaceuticals may suffer from the complex ligand chemistry required for Ga³⁺ complexation to useful tissue-specific radiopharmaceuticals.” Indeed, at that time (1994) no ⁶⁸Ga-labeled pharmaceuticals were in clinical studies, and currently still not one EMA- or FDA-approved ⁶⁸Ga-labeled

Acknowledgments

We would like to thank the COST working groups B12, D18, D38, BM0607, the Training School on Generators in Mainz, and many colleagues involved in these networks for stimulating discussions. Thanks to the cooperation and networking within COST, more than 40 centers in Europe use ⁶⁸Ge/⁶⁸Ga generators, also in clinical studies.

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68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives

Section snippets

Physical Characteristics of 68Ge, 68Ga, and the 68Ge/68Ga Generator

Purification and Eluate Concentration

68Ge Breakthrough

DOTA-Peptides Labeled With 68Ga

PK of 68Ga-labeled Pharmaceuticals

Specific Radioactivity

Robotics for Automated Labeling

Regulatory Affairs

Applications

Future Perspectives

Acknowledgments

Arch Biochem Biophys

Appl Radiat Isot

Int J Appl Radiat Isot

Appl Radiat Isot

Nucl Med Biol

Semin Nucl Med

Int J Appl Radiat Isot

Appl Radiat Isot

Appl Radiat Isot

Appl Radiat Isot

Nucl Med Biol

Int J Rad Appl Instrum B

Nucl Med Biol

Appl Radiat Isot

Semin Nucl Med

Chem Biol

Nucl Med Biol

Radiochemistry of germanium

Journal of Radioanalytical and Nuclear Chemistry

The renaissance of the Ge/Ga radionuclide generator initiates new developments in Ga radiopharmaceutical chemistry

Curr Top Med Chem

Ga2O for target, solvent extraction for radiochemical separation and SnO(2) for the preparation of a Ge-68/Ga-68 generator

Journal of Radioanalytical and Nuclear Chemistry

68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals

Contrast Media Mol Imaging

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

Eur J Nucl Med Mol Imaging

Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease

Chem Rev

Molecular imaging of HER2-expressing malignant tumors in breast cancer patients using synthetic 111In- or 68Ga-labeled affibody molecules

J Nucl Med

Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data

Eur J Nucl Med

68Ga-labelled DOTA-derivatised peptide ligands

Eur J Nucl Med Mol Imaging

Detection of unknown primary neuroendocrine tumours (CUP-NET) using (68)Ga-DOTA-NOC receptor PET/CT

Eur J Nucl Med Mol Imaging

Biodistribution of the Ga-68 labeled somatostatin analogue DOTA-NOC in patients with neuroendocrine tumors: characterization of uptake in normal organs and tumor lesions

Q J Nucl Med Mol Imaging

Changing role of somatostatin receptor targeted drugs in NET: nuclear medicine's view

J Pharm Pharm Sci

(68)Ga-labeled peptides in tumor imaging

J Nucl Med

68Ga-PET radiopharmacy: a generator-based alternative to 18F-radiopharmacy

Ernst Schering Res Found Workshop

Optimal buffer choice of the radiosynthesis of (68)Ga-Dotatoc for clinical application

Nucl Med Commun

The 68Ge/68Ga generator has high potential, but when can we use 68Ga-labelled tracers in clinical routine?

Eur J Nucl Med Mol Imaging

Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU

Eur J Nucl Med Mol Imaging

A new germanium-68/gallium-68 generator

J Nucl Med

Potential column chromatography generators for ionic Ga-68: I–inorganic substrates

J Nucl Med

Influence of preliminary treatment of aluminum oxide on the separation of Ge-68-Ga-68 radionuclide chain

Journal of Radioanalytical and Nuclear Chemistry

A new Ge-68/Ga-68 generator based on Ceo2

Journal of Radioanalytical and Nuclear Chemistry

A new generator for ionic gallium-68

J Nucl Med

Nanoceria-PAN composite-based advanced sorbent material: a major step forward in the field of clinical-grade 68Ge/68Ga generator

ACS Appl Mater Interfaces

Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities

Eur J Nucl Med Mol Imaging

Radiolabelling DOTA-peptides with 68Ga

Eur J Nucl Med Mol Imaging

⁶⁸Ga-labeled DOTA-Peptides and ⁶⁸Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives

Physical Characteristics of ⁶⁸Ge, ⁶⁸Ga, and the ⁶⁸Ge/⁶⁸Ga Generator

⁶⁸Ge Breakthrough

DOTA-Peptides Labeled With ⁶⁸Ga

PK of ⁶⁸Ga-labeled Pharmaceuticals

A new Ge-68/Ga-68 generator based on Ceo₂